Pediatric Annals

Atopic Dermatitis: Etiology and Pathogenesis

William L Weston, MD; J Clark Huff, MD

Abstract

INTRODUCTION

Atopic dermatitis represents a phenotype that is associated with a hereditary tendency to asthma and allergic rhinitis.1 However, no single abnormality has been uncovered that leads to the genesis of this dermatitis. The association of atopic dermatitis with diverse inborn errors of metabolism (Table I)2 suggests that the clinical features we appreciate as atopic dermatitis may be the result of numerous pathomechanisms.

The search for a common pathway in atopic dermatitis has led to three major theories: (1) immunologic excess, (2) immunodeficiency, and (3) the beta-blockade theory.

Table

1. Rajka. G. Atopic Dermatitis. Philadelphia: W. B. Saunders Company. 1 975.

2. Rostenberg, A.. Jr., and Solomon, L M. Infantile eczema and systemic disease. Arch. Dermatol- 98 (1968), 41-46.

3. Ishizaka, K., and Ishizaka, T. Biological function of IgE antibodies and mechanisms of reaginic hypersensitivity. Clin. Exp. Immunol. 6 (1970), 25-42.

4. Ogawa, M., et al. Immunoglobulin E in atopic dermatitis. Arch. Dermatol. 103 (1971), 575-580.

5. Jones, H. E., et al. Atopic disease and serum immunoglobulin E. Br. J. Dermatol. 92 (1975), 1726.

6. Clendenning, W. E., et al. Serum IgE studies in atopic dermatitis. J. Invest. Dermatol. 61 (1973). 233-236.

7. Johansson, S. G. 0.. and Juhlin, L Immunoglobulin E in "healed" atopic dermatitis, and after treatment with corticosteroids and azathbprine. Br. J. Dermatol. 82 (1970), 10-14.

S. McGready. S. J., and Buckley, R. H. Depression of cell-mediated immunity in atopc eczema. J. Allergy Clin. Immunol. 56 (1975), 393-406.

9. Geha, R. S.. et al. Cooperation between thymus-derived and bone marrow-derived lymphocytes in the antibody response to ragweed antigen E in vitro. J. Clin. Invest. 56 (1973), 386-390.

10. Hill, H. R., and Qu ie, P. G. Raised serum IgE levels and defective neutrophil Chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1 (1974), 183-186.

11. Rogge, J. L., and Hanifin, J. M. Depressed leukocyte Chemotaxis and lymphoctye transformation in severe atopic dermatitis. Clin. Res. 24 (1976), 974.

12. Szentivanyi, A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 42 (1968). 203-232.

13. Reed. C. E.. Busse. W. T., and Lee, T. P. Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis. J. Invest. Dermatol, (in press).

TABLE 1

INBORN DISORDERS ASSOCIATED WITH ATOPIC DERMATITIS

TABLE 2

IMMUNOLOGIC DEFECTS SUSPECTED IN ATOPIC DERMATITIS

TABLE 3

FACTORS EXACERBATING ATOPIC DERMATITIS…

INTRODUCTION

Atopic dermatitis represents a phenotype that is associated with a hereditary tendency to asthma and allergic rhinitis.1 However, no single abnormality has been uncovered that leads to the genesis of this dermatitis. The association of atopic dermatitis with diverse inborn errors of metabolism (Table I)2 suggests that the clinical features we appreciate as atopic dermatitis may be the result of numerous pathomechanisms.

The search for a common pathway in atopic dermatitis has led to three major theories: (1) immunologic excess, (2) immunodeficiency, and (3) the beta-blockade theory.

Table

TABLE 1INBORN DISORDERS ASSOCIATED WITH ATOPIC DERMATITIS

TABLE 1

INBORN DISORDERS ASSOCIATED WITH ATOPIC DERMATITIS

IMMUNOLOGIC-EXCESS THEORY

Following the discovery and characterization of the reaginic antibody immunoglobulin E (IgE),3 it was postulated that a chemical marker for the atopic state in general and atopic dermatitis in particular had been found. Serum IgE levels were reported elevated in atopic dermatitis,4 lending further support to its importance. However, it has now been clearly established that elevated serum IgE levels occur only in patients with the most severe dermatitis; levels are normal in those with mild or moderate atopic dermatitis.5 Intradermal skin tests with antibody to IgE result in the same urticarial response in atopic and nonatopic patients, demonstrating that there is not more IgE bound in atopic skin.4 Serum IgE levels, even when elevated, do not fluctuate with changes in atopic dermatitis activity.6 In particular, elevations of serum IgE do not precede flares in atopic dermatitis. Treatment sufficient to clear atopic dermatitis does not alter serum IgE levels.7 IgE injected into the skin results in wheal and flare but not dermatitis.3 The clinical use of immediate skin (prick) tests have been of little use in atopic dermatitis.1 To date, excessive production of IgE has not satisfactorily explained the pathomechanism of atopic dermatitis.

IMMUNODEFICIENCY

A number of immunologic defects have been reported in children with atopic dermatitis (Table 2).

Cell-mediated immunodeficiency. Certain patients with atopic dermatitis suffer depressed cellmediated immunity.8 They may be unresponsive to delayed skin tests and the potent sensitizer DNCB.* They have depressed numbers of circulating T lymphocytes and suppressed transformation of lymphocytes to mitogens. There is some evidence in laboratory animals and in man that T lymphocytes may regulate IgE production.9 Therefore, patients with depressed cell-mediated immunity would have excess serum IgE. Further work may clarify this interplay between T lymphocytes and IgE, particularly in relationship to atopic dermatitis.

Depressed phagocyte function. Atopic dermatitis patients with hyperimmunoglobulinemia E may have a newly described syndrome of atopic dermatitis, elevated serum IgE, recurrent staphylococcal pyodermas, and defective neutrophil and monocyte Chemotaxis.10 Such patients may also show chronic mucocutaneous candidiasis, asthma, and urticaria. Included in this group are children with Job's syndrome of Celtic complexion, atopic eczema, hyperextensible joints, and "cold" staphylococcal abscesses. The elevated serum IgE apparently does not interfere with neutrophil or monocyte Chemotaxis, but histamine may be the responsible agent.

Functional defects in three cell lines (T lymphocytes, neutrophils, and monocytes) may be present simultaneously in certain patients with atopic dermatitis.11 This may account for the increased susceptibility of such patients to certain infectious agents but does not provide satisfactory insight into the pathomechanism of their disease.

BETA-BLOCKADE THEORY

In 1968, Szentivanyi proposed that an acquired deficiency in betaadrenergic receptors at the cell membrane would account for the atopic state and the unusual pharmacologic responses seen in cases of atopic dermatitis.12 He postulated that both acetylcholine and histamine would release catecholamines, which would activate alpha-receptors to excess because there is a deficiency of betareceptors. This would account for the persistent vasoconstriction of the skin in children with atopic dermatitis and explain the paradoxical response to injected acetylcholine and diminished response to injected histamine. It would also clarify the pronounced vasoconstriction seen in atopic skin characterized by facial pallor, low skin temperature, and white dermographism. This has not been confirmed in the laboratory, since epidermal skin from atopic dermatitis patients contains normal levels of cyclic AMP, adenyl cyclase, phosphodiesterase, and protein kinase - necessary chemicals in beta-adrenergic function.13

Table

TABLE 2IMMUNOLOGIC DEFECTS SUSPECTED IN ATOPIC DERMATITIS

TABLE 2

IMMUNOLOGIC DEFECTS SUSPECTED IN ATOPIC DERMATITIS

Table

TABLE 3FACTORS EXACERBATING ATOPIC DERMATITIS

TABLE 3

FACTORS EXACERBATING ATOPIC DERMATITIS

OTHER FACTORS IN PATHOGENESIS

Most, if not all, dermatitis seen in children with atopic dermatitis may be the result of chronic rubbing and scratching of pruritic skin. A number of factors may account for increased pruritus in these children (Table 3).

Abnormal sweating. Many children with atopic dermatitis complain of increased itching during induced sweating. In areas of atopic dermatitis, sweat secretion is not diminished but sweat-duct occlusion is common.1 Occlusion of sweat-duct openings on the surface of the skin by keratinous plugs may account for later hypohidrosis. Extravasation of sweat into the dermis may account for some exacerbations related to sweating.

Dry skin. There is a strong association of dry skin with atopic dermatitis.1 Dry, asteatotic skin and horny follicular papules (keratosis pilaris) are common findings in atopic patients. Microscopic fractures of the stratum corneum during drying involve loss of the epidermal barrier and increased susceptibility to irritants. Dry skin occurring in the winter in cool climates is a significant factor in exacerbations of atopic dermatitis.1

Contact sensitivity. Children with atopic dermatitis may be extremely sensitive to certain contactants.1 They may experience bouts of itching and subsequent exacerbation of dermatitis when wool or an irritant chemical contacts the skin. Detergents and frequent soaping of the skin often result in prolonged itching. Sensitivity to contactants may partially explain localization of dermatitis in certain areas, particularly the hands and feet.

Stress and anxiety. Emotional stress indisputably leads to increased scratching. This frequently occurs in children either from heightened awareness of itching or from habitual scratching.1 Atopic dermatitis worsens during such episodes. It is important for the patient to realize that scratching the skin is a means of expressing anxiety. Removal of the child from his normal environment to a nonstressful situation has been recognized to be of great benefit to atopic dermatitis patients.1

SUMMARY

Atopic dermatitis is a recognizable phenotype that most likely results from several mechanisms. An increasing number of children with atopic dermatitis are recognized as having immune defects, although the exact incidence of such immunodeficiency states among patients with atopic dermatitis is unknown. Children with atopic dermatitis who suffer recurrent or persistent infections should undergo immunologic evaluation. Ideally, this should include evaluation of cell-mediated immunity as well as neutrophil and monocyte Chemotaxis. Further investigation into the beta-blockade theory may enhance our understanding of atopic dermatitis.

Careful attention to factors exacerbating atopic dermatitis is essential in understanding this problem. Abnormal sweating, dry skin, sensitivity to contactants, and emotional stress should always be considered in evaluation of children with atopic dermatitis.

BIBLIOGRAPHY

1. Rajka. G. Atopic Dermatitis. Philadelphia: W. B. Saunders Company. 1 975.

2. Rostenberg, A.. Jr., and Solomon, L M. Infantile eczema and systemic disease. Arch. Dermatol- 98 (1968), 41-46.

3. Ishizaka, K., and Ishizaka, T. Biological function of IgE antibodies and mechanisms of reaginic hypersensitivity. Clin. Exp. Immunol. 6 (1970), 25-42.

4. Ogawa, M., et al. Immunoglobulin E in atopic dermatitis. Arch. Dermatol. 103 (1971), 575-580.

5. Jones, H. E., et al. Atopic disease and serum immunoglobulin E. Br. J. Dermatol. 92 (1975), 1726.

6. Clendenning, W. E., et al. Serum IgE studies in atopic dermatitis. J. Invest. Dermatol. 61 (1973). 233-236.

7. Johansson, S. G. 0.. and Juhlin, L Immunoglobulin E in "healed" atopic dermatitis, and after treatment with corticosteroids and azathbprine. Br. J. Dermatol. 82 (1970), 10-14.

S. McGready. S. J., and Buckley, R. H. Depression of cell-mediated immunity in atopc eczema. J. Allergy Clin. Immunol. 56 (1975), 393-406.

9. Geha, R. S.. et al. Cooperation between thymus-derived and bone marrow-derived lymphocytes in the antibody response to ragweed antigen E in vitro. J. Clin. Invest. 56 (1973), 386-390.

10. Hill, H. R., and Qu ie, P. G. Raised serum IgE levels and defective neutrophil Chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1 (1974), 183-186.

11. Rogge, J. L., and Hanifin, J. M. Depressed leukocyte Chemotaxis and lymphoctye transformation in severe atopic dermatitis. Clin. Res. 24 (1976), 974.

12. Szentivanyi, A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 42 (1968). 203-232.

13. Reed. C. E.. Busse. W. T., and Lee, T. P. Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis. J. Invest. Dermatol, (in press).

TABLE 1

INBORN DISORDERS ASSOCIATED WITH ATOPIC DERMATITIS

TABLE 2

IMMUNOLOGIC DEFECTS SUSPECTED IN ATOPIC DERMATITIS

TABLE 3

FACTORS EXACERBATING ATOPIC DERMATITIS

10.3928/0090-4481-19761201-05

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